Multiple myeloma (MM) is the cancer of plasma cells within the bone marrow and remains incurable. Tumor-associated macrophages (TAMs) within the tumor microenvironment often display a pro-tumor phenotype and correlate with tumor proliferation, survival, and therapy resistance. IL-10 is a key immunosuppressive cytokine that leads to recruitment and development of TAMs. In this study, we investigated the role of IL-10 in MM TAM development as well as the therapeutic application of IL-10/IL-10R/STAT3 signaling inhibition. We demonstrated that IL-10 is overexpressed in MM BM and mediates M2-like polarization of TAMs in patient BM, 3D co-cultures in vitro, and mouse models. In turn, TAMs promote MM proliferation and drug resistance, both in vitro and in vivo. Moreover, inhibition of IL-10/IL-10R/STAT3 axis using a blocking IL-10R monoclonal antibody and STAT3 protein degrader/PROTAC prevented M2 polarization of TAMs and the consequent TAM-induced proliferation of MM, and re-sensitized MM to therapy, in vitro and in vivo. Therefore, our findings suggest that inhibition of IL-10/IL-10R/STAT3 axis is a novel therapeutic strategy with monotherapy efficacy and can be further combined with current anti-MM therapy, such as immunomodulatory drugs, to overcome drug resistance. Future investigation is warranted to evaluate the potential of such therapy in MM patients.

多发性骨髓瘤 （MM） 是骨髓内浆细胞的癌症，目前仍无法治愈。肿瘤微环境中的肿瘤相关巨噬细胞 （TAM） 通常表现出促肿瘤表型，并与肿瘤增殖、存活和治疗耐药性相关。IL-10 是一种关键的免疫抑制细胞因子，可导致 TAM 的募集和发育。在这项研究中，我们研究了 IL-10 在 MM TAM 发展中的作用以及 IL-10/IL-10R/STAT3 信号抑制的治疗应用。我们证明 IL-10 在 MM BM 中过表达，并介导患者 BM、体外 3D 共培养和小鼠模型中 TAMs 的 M2 样极化。反过来，TAM 在体外和体内促进 MM 增殖和耐药性。此外，使用阻断 IL-10R 单克隆抗体和 STAT3 蛋白降解剂/PROTAC 抑制 IL-10/IL-10R/STAT3 轴阻止了 TAM 的 M2 极化和随之而来的 TAM 诱导的 MM 增殖，并使 MM 对体外和体内治疗重新敏感。因此，我们的研究结果表明，抑制 IL-10/IL-10R/STAT3 轴是一种具有单药疗效的新型治疗策略，可以进一步与当前的抗 MM 疗法（如免疫调节药物）联合使用，以克服耐药性。有必要进行进一步的调查，以评估这种疗法在 MM 患者中的潜力。